Our ability to develop drugs to effectively treat musculoskeletal diseases like osteoporosis is limited by the absence of drug targets (genes) central to the etiology of these diseases. At present the number of genes known to regulate osteoblast maturation is limited. Our inability to readily identify these genes is due to the absence of an effective system by which these genes can be cloned from cDNA libraries via functional selection in vitro. Since traditional genetic selections are dependent on the survival and growth of cells that have acquired the appropriate phenotype following transformation (e.g. drug resistance) it has not been possible to apply these methods to terminally-differentiated nondividing cells (e.g. osteoblasts). The technological innovations that are the Aims of this program are the generation of 1) representative cDNA libraries in Vaccinia vector. 2) Mesenchymal progenitor cell line targets, which will be infected with the Vaccinia cDNA libraries to clone genes that regulate osteoblast maturation. And, 3) a new method by which cDNA expressed in cells infected by these Vaccinia libraries can be selected for by virtue of their ability to induce rapid cell death, thus permitting the use of terminally differentiated-nondividing cells as targets. The goal of this Phase I study is to focus on the osteoblast maturation system. The broad, long term objectives are to expand the system to all cell types. PROPOSED COMMERCIAL APPLICATIONS: The products to be developed by this research are the gene targets, which have recently sold for up to $20 million each, and the genetic selection system. Once the system is validated we will provide services for investigators who wish to have custom libraries made and screened in this unique expression vector.